Cytochrome P450 as Dimerization Catalyst in Diketopiperazine Alkaloid Biosynthesis. Issue 5 (13th February 2014)

• Record Type: Journal Article
• Authors: Saruwatari, Takayoshi; Yagishita, Fumitoshi; Mino, Takashi; Noguchi, Hiroshi; Hotta, Kinya; Watanabe, Kenji
• Is Part Of: Chembiochem. Volume 15:Issue 5(2014)
• Page Start: 656
• Page End: 659
• Publication Date: 2014-02-13
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201300751
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>As dimeric natural products frequently exhibit useful biological activities, identifying and understanding their mechanisms of dimerization is of great interest. One such compound is (−)‐ditryptophenaline, isolated from <italic>Aspergillus flavus</italic>, which inhibits substance P receptor for potential analgesic and anti‐inflammatory activity. Through targeted gene knockout in <italic>A. flavus</italic> and heterologous yeast gene expression, we determined for the first time the gene cluster and pathway for the biosynthesis of a dimeric diketopiperazine alkaloid. We also determined that a single cytochrome P450, DtpC, is responsible not only for pyrroloindole ring formation but also for concurrent dimerization of <italic>N</italic>‐methylphenylalanyltryptophanyl diketopiperazine monomers into a homodimeric product. Furthermore, DtpC exhibits relaxed substrate specificity, allowing the formation of two new dimeric compounds from a non‐native monomeric precursor, brevianamide F. A radical‐mediated mechanism of dimerization is proposed.</p> </abstract>